The invention pertains to a process for preparing carbetapentane tannate.
Carbetapentane is a well-known commercially available antihistamine. Its chemical name is 2-(diethylaminoethoxy)ethyl-1-phenyl-1-cyclopentanecarboxylate. Carbetapentane is an antitussive compound that is described in U.S. Pat. No. 2,842,845 and is structurally related to caramiphen. Due to its insolubility in water, carbetapentane is typically available in the form of its citrate salt which has a melting of 93xc2x0 C., and occurs as a white powder which is freely soluble in water and is slightly soluble in alcohol
Carbetapentane has an atropine-like action that depresses the cough reflex by selective central nervous system depression. Carbetapentane is frequently combined with one or more antihistaminic drugs such as pyrilamine. Such combination, in the form of their tannate salts is frequently administered orally for the symptomatic relief of coryza associated with the common cold, sinusitis, allergic rhinitis, unproductive cough and upper respiratory tract conditionsxe2x80x94see U.S. Pat. No. 6,306,904.
Antihistamine compounds in the form of their free bases as well as their salts, e.g., citrates, maleates, hydrobromides, hydrochlorides, tannates, etc., are well known. Antihistamines in the form of their tannate salts are very desirable because such salts are generally stable and two or more antihistamines is such form may be combined without any untoward side effects.
Tannic acid is commercially available and is used in many industrial applications. It is frequently referred to as gallotannic acid, gallotanin; glycerite or tannin. It is a pale tan powder having a decomposition point of 210-215xc2x0 C., and is highly soluble in water and alcohols. Its molecular formula is C76H52O46 and its CAS number is 1401-55-4. Tannic acid is typically produced from Turkish or Chinese nutgall and has a complex non-uniform chemistry and typically contains about 5-10 wt. % water.
Commercially available antihistamine tannate compositions are relatively impure. Such compositions are typically prepared by reacting the antihistamine free base with tannic acid in the presence of a volatile solvent, usually isopropanol. The yield is only fair (e.g. about 70%) and decomposition products e.g. 2-5 wt. %, and a significant amount of the volatile solvent, e.g. 6-10 wt. %, based on the weight of the composition, remains with the product and cannot be removed.
Typically, in the conventional isopropanol route, the antihistamine free base and the tannic acid will be present in the isopropanol at a concentration of about 20 wt. %, based on the weight of the reaction mixture. The reaction mixture is stirred for about one hour, while maintaining a temperature of 60-70xc2x0 C. The reaction mixture is cooled to room temperature and filtered. The precipitate is vacuum dried for an extended period of time at a temperature of 60-80xc2x0 C. A yield of product of only about 70% is obtained and the product purity will be about 85-90 wt. %, based on the weight of the composition (the impurities consist of isopropanol and decomposition products which cannot be removed).
Many antihistamine tannates are heat sensitive and therefore undergo decomposition quite readily upon prolonged exposures to temperatures as low as 50xc2x0 C. Accordingly, even when the solvent utilized in its preparation has a relatively high vapor pressure such as is in the case of isopropanol, it is impossible to reduce the solvent content below about 6 wt. %, based on the weight of the antihistamine tannate composition, even at reduced pressures and very mild elevated temperatures. Moreover, from an environmental point, it would be most desirable if the antihistamine tannate could be prepared such that the use of volatile solvents could be avoided.
The process disclosed in U.S. Pat. No. 5,663,415 represents a significant improvement over the isopropanol route. The process disclosed in the ""415 patent involves three steps:
(a) the antihistamine in the form of its free base is contacted with tannic acid in the presence of water at a maximum temperature which will not cause decomposition of the antihistamine tannate to an extent of greater than about 5 wt %, based on the weight of the antihistamine tannate;
(b) the antihistamine is allowed to remain in contact with the tannic acid in the presence of water for a period of time of about 5 minutes to 4 hours at said maximum temperature; and
(c) the antihistamine tannate resulting from step (b) freeze-dried at a temperature and at a reduced pressure and for such period of time that (i) at least about 90 wt. % of the water is removed from the antihistamine tannate and (ii) decomposition of the antihistamine tannate will be limited to a maximum of about 5 wt. %.
The ""415 patent discloses a three-step method that results in the production of pure antihistamine tannate compositions having a minimum purity level of at least 90 wt. %, usually at least 95 wt. % and often at least 98 wt. %, based on the weight of the composition, with a yield of at least about 90% and often with a yield in excess of 97%.
The chief xe2x80x9cimpurityxe2x80x9d present in the compositions prepared by the process of the ""415 patent is water which is present in an amount of 1-5 wt. %, based on the weight of the composition.
Although the process disclosed in the ""415 patent represents a dramatic improvement leading to very pure antihistamine tannate compositions, it has several drawbacks: freeze-drying is quite time-consuming(typically 30-36 hours to remove 1 liter of water) and expensive and requires specialized equipment in order to achieve the reduced pressures and temperature required to dry the antihistamine tannate composition, i.e., a pressure of not greater than about 500 miliTorr and a temperature in the range of about xe2x88x9260xc2x0 C. to xe2x88x9220xc2x0 C. Such specialized equipment also limits the amount of product that can be processed within a reasonable amount of time.
It has now been found that very pure carbetapentane tannate may be produced by a synthetic route which overcomes the drawbacks of the isopropanol and freeze-drying routes discussed above. The process of the invention avoids the use of aqueous and/or non-aqueous solvents or diluents and permits the rapid, inexpensive production of carbetapentane tannate having a purity level in excess of about 95 wt. %, and quite often a purity level in excess of 98 wt. %.
For the purposes of this invention, it is to be understood that the term xe2x80x9ccarbetapentanexe2x80x9d refers to the free base which is employed as the starting material in the process of the invention. If the carbetapentane is present in the form of a salt (typically a citrate), the salt is neutralized with a stoichiometric amount of a base such as sodium or potassium hydroxide and the resulting carbetapentane layer is washed free of salts.
The process of the invention involves the following steps:
(a) carbetapentane is heated to a temperature of up to about 120xc2x0 C.; and
(b) tannic acid is added to the carbetapentane while agitating the reaction mixture.
Preferably, the temperature of the carbetapentane is maintained in the range of about 80 to about 100xc2x0 C., e.g., 85 to 95xc2x0 C., during the addition of the tannic acid. In general, the tannic acid is slowly (e.g., over a period of 5 to 30 minutes) added to the carbetapentane which is continually agitated while the temperature is maintained in such range. Preferably, the reaction mixture is agitated for an additional period of about 10 minutes to about 2 hours after all of the tannic acid has been added to the carbetapentane, during which time such temperature range is maintained.
In general, the carbetapentane will be employed in an amount of about 1 to about 5 moles, preferably 2 to 4 moles, of carbetapentane per mole of tannic acid. If the reaction mixture proves to be too viscous for efficient agitation to occur, a small amount of water, e.g., 1-5 wt. %, may be added to the reaction mixture. However, it is preferred that the reaction between the carbetapentane and the tannic acid be carried out in the substantial absence of any aqueous or non-aqueous solvent or diluent.
The reaction mixture is subsequently cooled to room temperature and is thereafter milled to provide a free-flowing powder having a particle size in the range of about 50 to about 200 mesh. The resultant carbetapentane tannate is a light tan-colored powder having a softening point of 80-85xc2x0 C., a minimum purity of at least about 95 wt. % and it will be slightly soluble in water and soluble in alcohols and insoluble in methylene chloride. In contrast thereto, carbetapentane (free base) is a liquid which is insoluble in water, but is soluble in alcohols and methylene chloride, while tannic acid is a tan-colored powder is soluble in water and alcohols, but is insoluble in methylene chloride, while tannic acid has a decomposition point of 210-215xc2x0 C.
The carbetapentane tannate produced by the process of the invention may be used as is in antitussive pharmaceutical preparations or, if desired, it may be formulated with other pharmaceutically active ingredients such as antihistamines and antitussives, e.g., chlorpheniramine, brompheniramine, pyrilamine, phenylephrine, ephedrine, pseudo-ephedrine, dextromethorphan, guaifenesin, carbinoxamine, and the like. Typically, these other active ingredients will be employed in the form of their free bases or their salts, e.g., citrates, maleates, hydrobromides, hydrochlorides, tannates, etc.
The following nonlimiting examples will serve to illustrate the present invention.